Effects of Age and Antiepileptic Drugs on Plasma Levels and Kinetics of Clobazam and N‐Desmethylclobazam

Abstract

The authors monitored the plasma levels of clobazam (CLO) and its principal metabolite, N-desmethylclobazam (NCLO) during chronic treatment of more than 400 epileptic patients receiving different co-medications, such as phenytoin (PH), carbamazepine (CBZ), sodium valproate (VPA) and phenobarbital (PB). This study investigated the influence of age and antiepileptic drugs on plasma levels of CLO and NCLO. Plasma concentrations measured 3 hr after morning administration of CLO varied from 30 to 700 [formula; see text] for CLO, and from 160 to 7000 [formula; see text] for NCLO. Plasma levels of CLO were higher in patients aged 20-30 years. NCLO concentrations increased with age up to 20 years. Coadministered antiepileptic compounds significantly decreased maximal plasma levels of CLO. Moreover, PH and CBZ a significantly increased the plasma levels of NCLO. Results on the influence of CBZ on CLO kinetics were confirmed in a group of ten patients receiving PB and VPA and later PB, VPA and CBZ as CLO associated drugs. The influence of VPA on the pharmacokinetics parameters of CLO was also evaluated in a patient in the latter group.

GABAA Receptor Physiology and Its Relationship to the Mechanism of Action of the 1,5-Benzodiazepine Clobazam

“…In the same study, the half-life of N-CLB was significantly longer: 49 hours for adults with epilepsy and 57 hours for healthy volunteers. [24] Additional studies were recently conducted that used techniques based on current FDA guidance for these analyses to confirm the pharmacokinetic differences between clobazam and N-CLB. In these studies, clobazam demonstrated a rapid yet moderately variable oral absorption following a single 10 mg dose, with a median time to maximum plasma concentration (t max ) of 1.0 hours (42% coefficient of variation [CV]) and a range of 0.5-2.6 hours.…”

“…[22] Both clobazam and its active metabolite, N-desmethylclobazam (N-CLB), are metabolized in the liver via cytochrome P450 (CYP), primarily 2C19. [23] A 1990 report by Bun et al [24] evaluated the influence of age on clobazam pharmacokinetics in 17 patients with epilepsy (age range: 6-32 years) and 6 healthy volunteers (age range: 24-29 years). The half-life of clobazam was found to be shorter for patients with epilepsy (12 hours for adults and 16 hours for children with epilepsy), compared with 24 hours for healthy volunteers.…”

Therapeutic Drug Monitoring of Clobazam and Its Metabolite—Impact of Age and Comedication on Pharmacokinetic Variability

“…It has previously been suggested that both CLB and NCLB C/D ratios are lower in children, 28 reflecting higher clearance. Some mechanisms thought to lead to increased drug clearance in children (such as increased blood flow) would affect both metabolic steps equally.…”

Simultaneous determination of clobazam and its major metabolite in human plasma by a rapid HPLC method

“…1) [1]. Moreover, NDCLB is accumulated during long-term treatment achieving concentration levels up to 10-times greater than clobazam and therefore it may be an important factor in both therapeutic and toxic responses [1,5,6].…”